Joint effect of insulin signaling genes on insulin secretion and glucose homeostasis.
J Clin Endocrinol Metab
; 98(6): E1143-7, 2013 Jun.
Article
em En
| MEDLINE
| ID: mdl-23633196
ABSTRACT
CONTEXT Reduced insulin signaling in insulin secreting ß-cells causes defective insulin secretion and hyperglycemia in mice. OBJECTIVE:
We investigated whether functional polymorphisms affecting insulin signaling (ie, ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; and TRIB3 Q84R, rs2295490) exert a joint effect on insulin secretion and abnormal glucose homeostasis (AGH).DESIGN:
Insulin secretion was evaluated by 1) the disposition index (DI) from an oral glucose tolerance test (OGTT) in 829 individuals; 2) insulin secretion stimulation index (SI) in islets from nondiabetic donors after glucose (n = 92) or glibenclamide (n = 89) stimulation. AGH (including impaired fasting glucose and/or impaired glucose tolerance or type 2 diabetes; T2D) was evaluated in case-control studies from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) Consortium (n = 6607).RESULTS:
Genotype risk score, obtained by totaling individual weighted risk allele effects, was associated with the following 1) DI (P = .005); 2) glucose and glibenclamide SI (P = .046 and P = .009); or 3) AGH (odds ratio 1.08, 95% confidence interval 1.03-1.13; P = .001). We observed an inverse relationship between genetic effect and age at AGH onset, as indicated by a linear correlation between AGH-genotype risk score odds ratios and age-at-diagnosis cutoffs (R(2) = 0.80, P < .001).CONCLUSIONS:
Functional polymorphisms affecting insulin signaling exert a joint effect on both in vivo and in vitro insulin secretion as well as on early-onset AGH. Our data provide further evidence that abnormal insulin signaling reduces ß-cell function and impairs glucose homeostasis.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Glucose
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Homeostase
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Insulina
Tipo de estudo:
Observational_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article